treatment of sclerosis systemic

8/13/2019 treatment of sclerosis systemic

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Treatment of Scleroderma

Allen N. Sapadin, MD; Raul Fleischmajer, MD

The treatment of systemic sclerosis (scleroderma) is difficult and remains a great chal-

lenge to the clinician. Because the cause is unknown, therapies are directed to improve

peripheral blood circulation with vasodilators and antiplatelet aggregation drugs, to pre-

vent the synthesis and release of harmful cytokines with immunosuppressant drugs, and

to inhibit or reduce fibrosis with agents that reduce collagen synthesis or enhance collagenase pro-

duction. The purpose of this review is to critically analyze conventional and new treatments of sys-

temic sclerosis and localized scleroderma. The therapeutic options discussed for the treatment of sys-temic sclerosis include the use of (1) vasodilators (calciumchannel blockers[nifedipine], angiotensin-

converting enzyme inhibitors [captopril, losartan potassium], and prostaglandins [iloprost,

epoprostenol]), (2) immunosuppressant drugs (methotrexate, cyclosporine, cyclophosphamide, and

extracorporeal photopheresis), and (3) antifibrotic agents (D-penicillamine, colchicine, interferon

gamma, and relaxin). The treatment options reviewed for localized scleroderma include the use of

corticosteroids, vitamin D analogues (calcitriol, calcipotriene), UV-A, and methotrexate. Prelimi-

nary reports on new therapies for systemic sclerosis are also considered. These include the use of

minocycline, psoralenUV-A, lung transplantation, autologous stem cell transplantation, etaner-

cept, and thalidomide. Arch Dermatol. 2002;138:99-105

Scleroderma or systemic sclerosis (SSc) isa connective tissuedisease that affects vari-ous organ systems, including skin, gastro-intestinal tract, lungs, kidney, andheart. Theseverity of skin andinternal organ involve-mentmaycorrelate withthe clinical courseof the disease. Based on the degree of skininvolvement, SSc can be divided into lim-ited cutaneousSSc or diffuse cutaneousSSc.Limited cutaneous SSc is characterized bysclerodactylyor acrosclerosis, withdistal in-volvement of the extremities (distal to theelbows andknees) with or without face in-

volvement. This clinical picture comprisesRaynaud phenomenon,dysphagia,calcino-sis cutis, and telangiectasis; it is slowlyprogressiveandis frequently associatedwithanticentromere antibodies. The most se-vere complications are pulmonary hyper-tension and biliary cirrhosis. Diffuse cuta-neous SSc is more severe and showsproximal involvement of the extremities

(proximal to the elbows andknees), trunk,or both.1 Diffuse cutaneous SSc is often as-sociated with pulmonary interstitial fibro-sis,renal crises,andgastrointestinalinvolve-ment (dysphagia, hypomotility, and otherdisorders). Diffuse cutaneous SSc is fre-quently associated with Scl-70 (antitopo-isomerase) and nucleolar autoantibodies(polymerase I and III, fibrillarin).

The cause of SSc is unknown and isregarded as an autoimmune disease in-volving cellular and humoral immunity.Cellular infiltrates, perivascular or dif-

fuse, have been demonstrated in skin,lungs (alveolitis), smooth muscle cells,esophagus, ileum and jejunum, syno-vium, and liver.2 These cells consist of Tlymphocytes (CD4+, CD8+), B lympho-cytes, and other nonspecific inflamma-tory cells,such as macrophages,mast cells,and eosinophils. Adhesion molecules areinvolved in homing and retention of lym-phocytes and other inflammatory cells inthe tissues and may play a role in the for-From the Department of Dermatology, Mount Sinai School of Medicine, New York, NY.

REVIEW

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mation of cellular infiltrates in SSc.1-6 Vascular involve-ment in SSc affects mainly capillaries, arterioles. andsmallarteries. The vascular pathology consists of absence orreduction in capillaries and ectasia of capillaries (telan-giectases), often accompanied by an increase in endo-thelialcell proliferation.7 Soluble mediators, adhesion mol-ecules, and cytotoxic factors have been incriminated inthe mechanism of endothelial cell damage, includingplasma factor VIII (von Willebrand factor), transform-ing growth factor, platelet-derived growth factor, gran-

zyme A, vascular cell adhesion molecule-1, intercellularadhesion molecule-1, and endothelin-1.8

The mechanism of fibrosis in SSc is not fully un-derstood, although it is known that soluble mediators(transforming growth factor, platelet-derived growthfactor, interleukin [IL] 4, IL-6, tumor necrosis factor[TNF]) can affect the behavior of fibroblast growth,proliferation, collagen synthesis, and chemotaxis.9-11 Therole of humoral immunity in SSc is unknown, althoughabout 90% of patients with SSc show circulating anti-nuclear antibodies.12

The treatment of SSc is difficult and remains a chal-lenge to the clinician. The purpose of this review is tocritically analyze conventional and new treatments of SSc

and localized scleroderma and briefly review new thera-peutic approaches under current investigation.

TREATMENT OF SYSTEMIC SCLEROSIS

Skin Involvement

Vasodilators. Vasodilators are used in SSc to reducevaso-spasm (Raynaud phenomenon) and to improve periph-eral circulation (ischemia, gangrene) secondary to arte-rial blood vessel damage (Table 1).

Calciumchannel blockers inhibit smooth muscle cellcontraction by reducing the uptake of calcium, which isneeded for muscle contraction. There are 2 groups of cal-cium channel blockers: (1) the pyridine dicarboxylic ac-ids (nifedipine, nicardipine hydrochloride) and (2) thedimethoxyphenyls (verapamil hydrochloride, diltiazem).Nifedipine, in dosages ranging from 30 to 60 mg daily,reduces the severity of Raynaud phenomenon.13 More re-cently, it was shown that nifedipine was superior to bio-

feedback techniques in reducing the frequency of Raynaudphenomenon episodes.14 Nifedipine is well tolerated, andthe most common adverse effects are headaches, flush-ing, and edema of the feet and ankles. Nifedipine therapycan also be combined with antiplatelet aggregation drugs(low-dose aspirin) and dipyridamole(up to 400 mg daily,in slow increments).8 Pentoxifylline (400 mg, 3 timesdaily), alone or in combination with nifedipine, reducesblood viscosity by increasing red blood cell deformabil-ity and can be used to improve capillary function.

More recently, losartan potassium, an antagonist ofangiotensin II receptor type I, was found effective in thetreatmentof Raynaud phenomenon.15 In this study, a regi-men of losartan potassium, 50 mg daily, was compared

with nifedipine, 40 mg daily. After 2 weeks, both drugsreduced the severity of Raynaud phenomenon, but onlylosartan reduced the frequency of episodes. Losartan waswell tolerated, and the most commonadverse effects weredry cough, muscle cramps, back pain, dizziness, and in-somnia.

Prostaglandins are potent vasodilators. Iloprost is achemically stable prostacyclin antagonist that wasfound effective in the treatment of Raynaud phenome-non secondary to SSc. Iloprost induces prolonged vaso-dilation, reduces platelet aggregation, and promotesendothelial cell lining. The drug was administered bycontinuous intravenous infusion (2 ng/kg per minute)for 8 hours daily for 3 days.16 More recently, an oral

preparation of iloprost was used for the treatment ofRaynaud phenomenon.17 A study comparing iloprost,50 to 150 g daily, vs placebo noted a decrease in dura-tion and severity of Raynaud phenomenon episodes,although the difference was not statistically significant.Another study18 involving 103 patients showed signifi-cant improvement in duration and severity of attacksbut not in frequency, compared with the placebo. How-ever, a third multicenter study19 involving 308 patientsshowed that oral iloprost, 50 g twice daily, was no bet-ter than the placebo.

Immunosuppressant Drugs.Because there is evidencefor activation of cellular and humoral immunity in SSc,

several immunosuppressant drugs have been previ-ously used, with questionable benefits, including pu-rine antimetabolites (6-thioguanine, azathioprine) andalkylating agents (chlorambucil, cyclophosphamide).20

More recently, investigations have been carried out withmethotrexate, cyclosporine, cyclophosphamide, and ex-tracorporeal photopheresis.

A controlled, parallel randomized, double-blind trialwith chlorambucil vs placebo was carried out involving64 patients with SSc. After a 3-year follow-up, chloram-bucil had obtained no better results than the placebo.21

Table 1. Treatment of Systemic Sclerosis

Vasodilators

Raynaud phenomenon

Nifedipine, verapamil hydrochloride

Losartan potassium

Iloprost

Pulmonary hypertension

Epoprostenol

Iloprost (carboprostacyclin)

Captopril

Renal crises

Captopril

Enalapril maleate (Vasotec)

Kidney dialysis

Kidney transplantation

Immunosuppressants

Skin induration

Methotrexate

Cyclosporine

Interstitial lung disease

Cyclophosphamide

Antifibrotics

Skin induration

D-Penicillamine

Colchicine

Interferon gammaRelaxin





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Methotrexate was used in a randomized, double-blind trial involving 29 patients with SSc. Patients re-ceived weekly injections of 15 mg of methotrexate or pla-cebo, and the dosage was increased to 25 mg per week forpoor responders. After a 24-week follow-up, significantimprovement was noted in skin induration and handgripstrength.22 Additional trials involving larger numbers ofpatients are necessary to confirm these results. Before ini-tiating methotrexate therapy, a thorough evaluation of the

patient should be completed. Baseline laboratory testsshould include complete blood cell count, platelet count,liver function tests, serum urea nitrogen, creatinine, andcreatinine clearance.

Cyclosporine is an immunosuppressive drug thatselectively inhibits the release of IL-2 from activated Tlymphocytes. There is evidence that serum levels of IL-2,its soluble receptors, or both are frequently elevated inearly SSc.23,24 An open clinical trial with cyclosporine wasconducted in 10 patients with SSc.25 The starting dosagewas 1 mg/kg per day, which was increased progressivelyuntil toxicity appeared or when 5 mg/kg per day wasreached. After 48 weeks follow-up, there was a de-crease in skin induration but no improvement in pul-

monary or cardiac involvement. Nephrotoxicity was fre-quent but usually transient and appeared mainly inpatients receiving more than 3 to 4 mg/kg per day.25

Because renal involvement in SSc is not uncom-mon, cyclosporine in thetreatment of SSc should be usedwith great caution. Patients must be carefully moni-tored for the development of nephrotoxicity, hyperten-sion, and malignant neoplasm, particularly lymphoma.Many drug interactions occur, and the patient should bequestioned about concomitant medications.

Extracorporeal photopheresis has been used to treatSSc. The principle of this technique is to administer oral6-methoxypsoralen, followed by extracorporeal activa-tion of lymphocytes by UV-A. The blood carrying cova-

lently cross-linked DNA-psoralen lymphocytes is thentransferred into the patient to elicit a specific immuneresponse that may block proliferation of certain T-lymphocyte clones. An initial multicenter trial was en-couraging and showed significant improvement in skininduration but no effect on pulmonary function.26 How-ever, additional trials questioned the efficacy of extra-corporeal photopheresis.27 Furthermore, extracorpo-real photopheresis for SSc is not approved by the Foodand Drug Administration.

Anotherapproach forimmunosuppression in SScwastheuse of antithymocyte globulin (3-5 mg/kg for 5 days).After 6 months follow-up, no improvement in skin scoreor pulmonary function was noted compared with a pla-

cebo group.28Corticosteroids are not useful in improving or pre-

venting the progression of skin involvement in SSc. How-ever, they may be helpful in controlling pain caused byarthralgia or myalgia. Similar benefits can be achievedwith nonsteroidal antiinflammatory agents.

Antifibrotic Agents.Fibrosis consists of massive depo-sition of newly synthesized connective tissue, mostly col-lagens, which is frequently responsible for the develop-ment of organ insufficiency. Fibrosis is a prominentfeature

in SSc and can develop in other disorders, such asatherosclerosis, cirrhosis of the liver, and idiopathic orsecondary pulmonary fibrosis. Pharmacodynamics of an-tifibrotic agents are geared (1) to reduce synthesis, ex-cretion, or polymerization of collagen fibrils, (2) to en-hance collagenase activity, and(3)to neutralize cytokinescapable of stimulating collagen synthesis, such as trans-forming growth factor, IL-4, and IL-6.

D-Penicillamine is a copper chelating agent that also

blocks aldehyde groups involved in intermolecular andintramolecular cross-linkages of collagen. Early clinicaltrials showed that D-penicillamine was beneficial in thetreatment of SSc, resulting in skin softening, slower pro-gression of internal involvement, fewer renal crises, andincreased survival time.29 The usual dosage was 250 mg,3 times daily. Several adverse effects may occur, includ-ing bone marrow depression, nephrotic syndrome, gas-trointestinal distress, and skin reactions, such as pem-phigus vulgaris. A recent multicenter, double-blind,randomized clinical trial was conducted in 134 patientswith diffuse SSc of early (18 months) duration. Onegroup of patients received 750 to 1000 mg of D-penicillamine daily, while the other group was treated

with 125 mg every other day. After 24 months follow-up,there wereno statistical differences between thegroupsin skin score (induration), incidence of renal crises, orsurvival time.30 Furthermore, 80% of adverse effects oc-curred in the high-dosage group. This study raises seri-ous questions about the therapeutic efficacy of D-penicillamine in SSc. However, if patients are treated withD-penicillamine, there is no advantage in using more than125 mg every other day.

Colchicine has been suggested for the treatment ofSSc, based on the rationale that it interferes with colla-gen synthesis by depolymerizing microtubules, reducesfibroblast proliferation, enhances collagenase activity,andhas some antiinflammatory properties.31 An early un-

controlled study32

involved 19 patients with a follow-upof 19 to 57 months. This study noted improvement inskin elasticity, mouth opening, and finger motility, anda reductionin dysphagia. Themean dosage is 0.6mg twicedaily. The drug is well tolerated, and the main adverseeffectis diarrhea.Blood cell countsandliver function testsshould be performed periodically for patients receivinglong-termtherapy. It is unfortunate that double-blindpla-cebo-controlled clinical trials are not available.

Interferon gamma has been shown in vitro to re-duce collagen production and interfere with fibroblastproliferation. Interferon alfa also inhibits collagen pro-duction but to a lesser degree than interferon gamma.11

Early investigations in the treatment of SSc with inter-

feron gamma or interferon alfa showed a modest im-provement in skin score.11 Recent multicenter clinical tri-als were carried out with recombinant interferon gamma(50 g subcutaneously, 3 times weekly for 1 year)33 orwith recombinant interferon gamma (0.01 mg/m2 per dayfor 18 weeks).34 Both studies showed a modest improve-ment in skin score. Adverse effects were common, mostlyconsisting of a flulike syndrome. Another multicenter,randomized controlledclinical trial withinterferon gammaconcluded that this drug hasmild beneficial effects in skinsclerosis and disease-associated symptoms.35 A 1-year





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double-blind placebo-controlledtrial with interferon alfashowed no benefit in the treatment of scleroderma, andin some patients it was deleterious.36

Relaxin is a pregnancy polypeptide, cytokine growthfactor that in vitro decreases the synthesis and secretionof interstitial collagens, blocks transforming growth fac-tor overexpression of type I and II procollagens, in-creases overexpression of matrix metalloproteinases, andreduces the production of tissue inhibitor of metallopro-

teinases.37

Early investigations using porcine-derived re-laxin in the treatment of SSc were inconclusive. How-ever, recently, a multicenter, randomized, double-blindclinical trial was carried out with human recombinantrelaxin. Sixty-eight patients with moderate to severe dif-fuse SSc of less than 5 years duration received 25 or 100g/kg per day or a placebo, both administered by con-tinuous subcutaneous infusion for 24 weeks. Patientsreceiving relaxin showed improvement in skin indura-tion, oral aperture, hand extension motion, and pulmo-nary forced vital capacity. Adverse effects consisted ofmenometrorrhagia, reversible anemia, and irritation andfocal infections at the site of the subcutaneous drug de-livery.38 However, additional follow-up observation did

not corroborate the efficacy of relaxin, and the study wasdiscontinued.

Kidney Involvement

Angiotensin-converting enzyme (ACE) inhibitors, in-cluding captopril and enalapril maleate, have been shownto be effective in controlling high blood pressure in SScsecondary to renal crisis. Furthermore, early treatmentmay prevent the onset of renal failure.39 In addition, oralcaptopril in dosages of 12.5 to 50 mg daily may reducepulmonary vascular resistance during pulmonary hyper-tension.40

A retrospective study41 on renal transplantation in SSc

gave encouraging results. Thedata were obtainedfrom theUnitedNetwork for Organ Sharing Scientific Renal Trans-plant Registry. Eighty-six patients with SSc from 1987 to1997 received renal transplants. After a 5-year follow-up,47% of the patients were alive, and the 5-year graft sur-vival was similar to that seen with renal transplantationin patients with systemic lupus erythematosus. This studysuggests that patients with severe renal insufficiency whodo not improve after receiving angiotensin-converting en-zyme inhibitors or kidney dialysis should be consideredas candidates for renal transplantation.

Lung Involvement

Epoprostenol is an arachidonic acid, naturally occur-ring prostaglandin with vasodilator activity and inhibi-tory effect on platelet aggregation.Epoprostenol wasusedby continuous intravenous infusion in 111 patients withmoderate to severe pulmonary hypertension secondaryto SSc. After 2 weeks of treatment, there was improvedexercise capacity and cardiopulmonary hemodynamics.There was also improvement in the severity of Raynaudphenomenon and healing of digital ulcers. Adverse ef-fects included jaw pain, nausea, and anorexia. Local com-plications consisted of sepsis, cellulitis, hemorrhages, and

pneumothorax (4% incidence for each condition).42 In-travenous iloprost was also effective in the treatment ofpulmonary hypertension.43

Cyclophosphamide alone or in combination withlow-dose prednisone was found effective in the treat-ment of severe interstitial lung disease in SSc.44,45 Morerecently, cyclophosphamide was used in a retrospectivecohort study46 involving 103 patients with SSc associ-ated with lung inflammation (alveolitis) proved by bron-

choalveolar lavage or by lung biopsy. The dosage con-sisted of 1 to 1.5 mg/kg per day orally to up to 2 mg/kgper day. In addition, they received intravenous cyclo-phosphamide, 800 to 1400 mg monthly, for 6 to 9 months.The patientstreated with cyclophosphamide showed sta-bilization of forced vital capacity and carbon monoxidediffusing capacity. Improvementin survival wasalso dem-onstrated. Myelosuppression, bladder toxicity (hemor-rhagic cystitis, bladder carcinoma), and carcinogenicityare complications of cyclophosphamide therapy. Base-line monitoring includes complete blood cell count withdifferential and platelets, serum chemistry profile, andurinalysis.

NEW THERAPIESPRELIMINARY REPORTS

Minocyline

Eleven patients with early SSc were treated with mino-cycline (100 mg daily for 4 weeks; 200 mg daily for 11months). Complete resolution of skin involvement wasnotedin 4 patients following 9 and 12 months of therapy.The mechanism of action of minocycline in SSc remainsunknown.47 This is an unexpected result and should bepursued further with controlled trials.

PsoralenUV-A

A small uncontrolled study48

treated 4 patients with SScwith psoralenUV-A (total dosage, 3.5-9.6 J/cm2). All pa-tients showed significant improvement in skin indura-tion, hand closure, and flexion range of fingers and kneejoints. Because UV-A was also shown to improve local-ized scleroderma (see thePsoralenUV-AandUV-A sub-section of the Treatment of Localized Scleroderma sec-tion), further controlled clinical trials are warranted.

Lung Transplantation

In a recent study,49 6 patients with limited cutaneous SScand 1 with diffuse SSc underwent lung transplantation.Five patientswerealive after a follow-up of2 to 15 months.

These results compare favorably with the overall sur-vival reported for lung transplantation. Furthermore, 3patients maintained satisfactory forced vital capacity(53%-71%). This study suggests that lung transplanta-tion is a feasible procedure and may prolong survival ofpatients with both SSc and severe lung involvement.

Oral Etretinate

Thirty-two patientswithchronic graft-vs-host diseasewhodidnot respond to previous therapieswere treated with oral





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etretinate in an open clinical trial. Among 27 patients whocompleted 3 months of therapy, 24 showed improvementin skin induration, flattening of cutaneous lesions, in-creased range of motion, and improvement in perfor-mance status.50 Becausesclerodermalike lesions in chronicgraft-versus-host disease closely resemble SSc, a con-trolledclinical trial investigating the useof etretinate in thetreatment of SSc may be desirable.

Autologous Stem Cell Transplantation

Autologous stem cell transplantation has been suggestedfor the treatment of autoimmune disease. Such a proce-dure was carried out in a 10-year-old patient with SSc of6 years duration who did not respond to various forms oftherapy. This patient was conditioned with CD34+ selec-tion, cyclophosphamide, and infusionof a CAMPATH-1Gmonoclonal antibody. After 2 yearsfollow-up, there wasa 50% improvement in skin score, disappearance of exer-tional dyspnea and alveolitis, andimprovement in growthrate.51 Another study52 included 8 patients with severe SSctreated with high-dose immunosuppressive therapy andradiation, followed by autologous stem cell transplanta-

tion. After a 1-year follow-up, 5 patients were alive andshowed improvement in skin score and in results on amodified Health Assessment Questionnaire, while pul-monary function remained stable. Two patients diedfrom interstitial pneumonitis, probably related to radia-tion toxicity.

Etanercept

Tumor necrosis factor is a proinflammatory cytokineproduced by activated T cells and macrophages. Tumornecrosis factor stimulates the synthesis of other pro-inflammatory cytokines (IL-1, IL-8, IL-6, and granulocyte-macrophage colony-stimulating factor), promotes fibro-

blast proliferation, and enhancesmatrix metalloproteinaseactivity. Specificblocking agents against TNF-havebeendeveloped, including monoclonal antibodies (inflix-imab)53 and a fusion protein of soluble TNF receptorlinked to human immunoglobulin (etanercept).54 Etaner-cept has been shown to be effective in various forms ofarthritis. In a preliminary pilot study,55 10 patients withdiffuse SSc were treated with etanercept, 25 mg subcu-taneously, twice weekly. After 6 months of therapy, therewas improvement in skin score (4 patients) and healingin digital ulcers, while pulmonary function remainedstable. The patientssense of well-being improved, andtolerance was good.

Thalidomide

Because thalidomide may be effective in treating chronicgraft-versus-host disease, it was also used in an open trialinvolving 10 patients with SSc. There was improvementin skin repigmentation, healing of digital ulcers, re-growth of hair, and a decrease in gastrointestinal re-flux.56 Histopathological examination of skin suggesteda reduction in fibrosis. Immunologic studies revealed up-regulation of CD4+ ligand in T cells and increased ex-pression of IL-2 and IL-8.

TREATMENT OF LOCALIZED SCLERODERMA

Localized scleroderma is a connective tissue disorder thataffects the skin and subcutaneous tissue. The disease oc-

curs in children and adults and, clinically, can be di-vided into morphea, localized or diffuse, deep morphea,and a linear form that usually affects arms and legs. His-topathological examination reveals an early inflamma-tory stage consisting mostly of mononuclear cell infil-trates and a late stage of severe fibrosis.57 Although thecause of localized scleroderma remains unknown, an au-toimmune mechanism is suspected because of its fre-quent association with antinuclear antibodies, rheuma-toid factor, antisingle-stranded DNA, and antihistoneantibodies.58 Although spontaneous resolution is pos-sible, the disease may cause severe functional (muscleatrophy) and cosmetic (severe scarring) disability, par-ticularly in children during the growing stage. The treat-

ment is difficult, although new therapeutic approachesappear encouraging (Table 2).

Topical Corticosteroids

Topical corticosteroids (fluorinated,medium potency, andhydrocortisone) may be of some help during the earlyinflammatory stage, although controlled clinical trials arenot available. Intralesional triamcinolone, 5 mg/mL, oncea month for 3 months, may improve or stop the progres-sion of morphea andlinear scleroderma affecting thescalpand forehead (coup de sabre).

Calcitriol and Calcipotriene

Calcitriol (1,25-dihydroxyvitamin D3) and calcipo-triene are analogues of vitamin D and have been used forthe treatment of psoriasis. Both compounds have a simi-lar receptor binding and affinity, although calcipotrieneis less potent and has minimal effects on calcium me-tabolism. Besidesaffecting keratinocyte differentiationandproliferation, calcitriol also inhibits fibroblast prolifera-tion, collagen synthesis, and, possibly, T-lymphocyte ac-tivation.59 Oral calcitriol, in dosages of 0.50 to 0.75 gdaily, improved joint mobility and skin extensibility in

Table 2. Treatment of Localized Scleroderma

Morphea

Corticosteroids (topical and intralesional)

Topical calcipotriene

Linear scleroderma

Corticosteroids (intralesional for coup de sabre)

PsoralenUV-A baths

UV-A alone (340-400 nm)

Oral calcitriol

Topical calcipotriene

Widespread morphea

PsoralenUV-A baths

UV-A alone (340-400 nm)

Oral calcitriol

Methotrexate

Methotrexate plus corticosteroids





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adult patients with generalized morphea, following 3 to 7months of therapy.60 In a more recent study,59 7 childrenwith linear scleroderma were treated with this agent, and5 showedan excellent response.Because oral calcitriol mayhavea dose-dependent effect on calciummetabolism,moni-toring of serum and urine calcium, inorganic phosphate,creatinine, and urea is advised, particularly when treat-ing children.59

Topical calcipotriene ointment (0.005%) was usedin

12 patients aged 12 to 38 years with biopsy-documentedactive morphea or linear scleroderma. After 3 months oftherapy, all patients showed improvement, including de-creases in erythema, telangiectases, and depigmenta-tion.61 The ointment was well tolerated, and there wereno adverse effects. Furthermore, there were no alter-ations in calcium metabolism as measured by serum lev-els of ionized calcium, parathyroid hormone, 1,25-dihydroxyvitamin D3, andurinary calcium excretion. Theseresults are encouraging but will have to be confirmed bya controlled clinical trial.

PsoralenUV-A and UV-A

PsoralenUV-A bath phototherapy has been shown to beeffective in the treatment of widespread morphea and lin-ear scleroderma.62 In this study, 17 patients were evalu-ated clinically and by ultrasound before and after treat-ment. The patients were immersed for 20 minutes in awarm water bath containing 1 mg/L of methoxsalen, fol-lowed by UV-A exposures, 0.2 to 0.5 J/cm2, increased ev-ery third day to a maximum tolerable dosage of 1.2 to 3.5J/cm2. After about 15 treatments, clearance or markedim-provement was noted in 13 of 17 patients. More recently,it has been reported that marked improvement wasachievedin 18(75%)of 24 patientsbyusing low-doseUV-Aalone in the range of 340 to 400 nm, 20 J/cm2, toa cumu-lativedosageof 600J/cm2.63 Two patients in this series with

subcutaneous localized scleroderma failed to respond toUV-Atherapy. Histopathological findings corroboratedtheclinical results. Although the mechanism of UV-A in lo-calized scleroderma is unknown, it is noteworthythe UV-Amay activate interstitial collagenases.64

Methotrexate

It is known that methotrexate is an effective drug for thetreatment of rheumatoid arthritis and juvenile rheuma-toidarthritis.65 Adult widespread morphea hasbeen treatedwith oral methotrexate, 15 mg/wk, and the dosage wasincreased to 25 mg/wk in resistant cases. After 24 weeksof therapy, 6 of 9 patients showed significant improve-

ment in skin induration. There were no serious adversereactions.66 Ten patients with active localized sclero-derma (mean age, 6.8 years) of 4 yearsmean durationwere treatedwith methotrexate (0.3-0.6 mg/kg per week)combined withpulse intravenous methylprednisolone(30mg/kg for 3 days monthly). Following 3 months of treat-ment, 9 patientsshowedsignificantbenefit, and there wereno serious adverse effects.67 Although these data appearinteresting, the use of methotrexate alone or in combi-nation with corticosteroids will have to be restricted tochildren with severe active, disabling disease.

CONCLUSIONS

Although research continues to contribute to our under-standing of the pathogenesis of SSc, its cause is still un-known. Present therapies are directed (1) to improve pe-ripheral blood circulationwithvasodilators and antiplateletaggregation drugs, (2) to prevent the synthesis and re-lease of harmful cytokines withimmunosuppressants,and(3) to inhibit or reduce fibrosis with agents that interfere

with collagen synthesis or enhance collagenase produc-tion. Although some progresshas been achieved, the treat-ment of scleroderma remains a challenge to the clinician.Further elucidation of the events that precipitate the ini-tial activation of theimmune system in this disease is cru-cial for the emergence of new therapeutic approaches.

Accepted for publication May 2, 2001.Corresponding author: Raul Fleischmajer, MD, De-

partment of Dermatology, Mount Sinai School of Medi-cine, 1425 Madison Ave, PO Box 1047, New York, NY 10029(e-mail: [email protected]).

REFERENCES

1. Leroy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis) clas-

sification, subsets and pathogenesis.J Rheumatol. 1988;15:202-205.

2. Fleischmajer R, Perlish JS, Reeves JRT. Cellular infiltrates in scleroderma skin.

Arthritis Rheum. 1977;20:975-984.

3. NeedlemanBW. Increasedexpression of intracellularadhesionmolecule I on the

fibroblasts of scleroderma patients.Arthritis Rheum. 1990;33:1847-1851.

4. Gruschwitz M, von Den Driesch P, Kellner P, et al. Expression of adhesion pro-

teins involved in cell-cell and cell-matrix interactions in the skin of patients with

progressive systemic sclerosis.J Am Acad Dermatol. 1992;27:169-177.

5. Gruschwitz MS, Hornstein OP, van den Driesch P. Correlation of soluble adhe-

sion molecules in the peripheral blood of scleroderma patients with their in situ

expression and with disease activity.Arthritis Rheum. 1995;38:184-189.

6. WhiteB. Immunopathogenesisof systemic sclerosis. Rheum Dis ClinNorthAm.

1996;22:695-708.

7. Fleischmajer R, Perlish JS. [3H]Thymidine labeling of dermal endothelial cells in

scleroderma.J Invest Dermatol. 1977;69:379-382.8. Leroy EC. Systemic sclerosis:a vascular perspective. RheumDis Clin NorthAm.

1996;22:675-694.

9. Fleischmajer R, Perlish JS, Krieg T, Timpl R. Variability in collagen and fibro-

nectin synthesis by scleroderma fibroblasts in primary culture.J Invest Derma-

tol. 1981;76:400-403.

10. Postlethwaitte AE. Early immune events in scleroderma. Rheum Dis Clin North

Am. 1990;16:125-139.

11. Jimenez SA,Hitraya E, Vargas J. Pathogenesis of scleroderma: collagen.Rheum

Dis Clin North Am. 1996;22:647-674.

12. Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma).Rheum Dis

Clin North Am. 1996;22:709-735.

13. Rodeheffer RJ, Rommer JA, Wigley F, Smith CRN. Controlled double-blind trial

of nifedipine in the treatment of Raynaud s phenomenon.N Engl J Med. 1983;

308:880-883.

14. Raynauds Treatment Study Investigators. Comparison of sustained-release ni-

fedipine and temperature biofeedback for treatment of primary Raynaud phe-

nomenon: results from a randomized clinical trial with 1-year follow-up. ArchIntern Med. 2000;160:1101-1108.

15. Dziadzio M, DentonCP, Smith R, Blann HK,BowersE, Black CM.Losartan therapy

for Raynauds phenomenon and scleroderma: clinical and biochemical findings

in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum.

1999;42:2646-2655.

16. Rademaker M, Cooke ED, Almond NE, et al. Comparison of intravenous infu-

sions of iloprost and oral nifedipine in treatment of Raynaud s phenomenon in

patients with systemic sclerosis: a double blind randomised study. BMJ. 1989;

298:561-564.

17. Belch JJ, Capell HA, Cooke ED, et al. Oral iloprost as a treatment for Raynaud s

syndrome:a double blind multicentreplacebocontrolled study. AnnRheum Dis.

1995;54:197-200.





7/7

18. Black CM, Hazkier-Sorensen L, Belch JJ, et al. Oral iloprost in Raynauds phe-

nomenon secondary to systemic sclerosis: a multicenter, placebo-controlled

dose-comparison study.Br J Rheumatol. 1998;37:952-960.

19. Wigley FM, Korn JN, Csuka ME, et al. Oral iloprost treatment in patients with

Raynauds phenomenon secondary to systemicsclerosis:a multicenter,placebo-

controlled, double-blind study.Arthritis Rheum. 1998;41:670-677.

20. Steigerwald JC. Chlorambucil in the treatment of progressive systemic sclero-

sis. In: Block CM, Myers AR, eds. Systemic Sclerosis (Scleroderma). New York,

NY: Gower Medical Publishing Ltd; 1985:423-427.

21. Furst DE, Clements PJ, Hill S, et al. Immunosuppression with chlorambucil ver-

susplacebofor scleroderma:resultsof a three-year parallel, randomized,double-

blind study.Arthritis Rheum. 1989;32:584-593.

22. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de

Putte LB. Comparison of methotrexate with placebo in the treatment of sys-

temic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week

observational trial.Br J Rheumatol. 1996;35:364-372.

23. Degiannis D, Seibold JR, Czarnecki M, Raskova J, Raska K. Soluble interleu-

kin-2 receptors in patients with systemic sclerosis: clinical and laboratory cor-

relation.Arthritis Rheum. 1990;33:375-380.

24. NeedelmanBW, Wigley FM, StairRW. Interleukin-1, interleukin-2, interleukin-4,

interleukin-6, tumor necrosis factorand interferon-levels in sera from pa-

tients with scleroderma.Arthritis Rheum. 1992;35:67-72.

25. Clements PJ, Lachenbruch PA, Sterz M, et al. Cyclosporine in systemic sclero-

sis.Arthritis Rheum. 1993;36:75-83.

26. RockAH, Freundlich B, JegasothyBV, et al.Treatmentof systemic sclerosiswith

extracorporeal photochemotherapy: results of a multicenter trial. Arch Derma-

tol. 1992;128:337-346.

27. Enomoto DN, Mekkes JR, Bossyt PM, et al. Treatment of patients with systemic

sclerosis with extracorporeal photochemotherapy (photopheresis). J Am Acad

Dermatol. 1999;41:915-922.

28. Sinclair HD, Williams JD, Rahman MA. Clinical efficacy of antithymocyte globu-

lin in systemic sclerosis:results of a placebo-controlled trial[abstract]. Arthritis

Rheum. 1994;36(suppl):s217.

29. Steen VD, Medsger TA Jr, Rodnan GP. D-penicillamine therapy in progressive

systemicsclerosis (scleroderma): a retrospective analysis. AnnInternMed. 1982;

97:652-659.

30. Clements PJ,Furst DE,Wong WK,et al.High-doseversuslow-doseD-penicillamine

in early diffuse systemic sclerosis.Arthritis Rheum. 1999;42:1194-1203.

31. Chetrit-Ben E, Levy M. Colchicine: 1998 update.Semin Arthritis Rheum. 1998;

28:48-59.

32. Alarcon-Segovia D, Ramos-Niembro F, Ibanez de Kasep G, Alocer J, Perez-

Tamayo R. Long-term evaluation of colchicine in the treatment of scleroderma.

J Rheumatol. 1979;6:705-712.

33. Hunzelmann N, Anders S, Fierlberg G, et al. Systemic scleroderma: multicenter

trial of 1 year of treatment with recombinant interferon gamma.Arch Dermatol.

1997;133:609-613.

34. Polisson RP, Gilkeson GS, Pyun EH, Pisetsky DS, Smith EA, Simon LS. A mul-

ticenter trial of recombinant human interferon gamma in patients with systemic

sclerosis: effects on cutaneousfibrosisand interleukin 2 receptor levels. J Rheu-

matol. 1996;23:654-658.

35. Grassegger A, Schuler G, Hessenberger G, et al. Interferon-gamma in the treat-

ment of systemic sclerosis: a randomized controlled multicentre trial.B r

J Dermatol. 1998;139:639-648.

36. Black CM, Silman AJ, Herrick AI, et al. Interferon-alpha does not improve out-

come at one year in patients with diffuse cutaneous scleroderma: results from a

randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42:

299-305.

37. Unemori EN,PickfordLB, Salles AL,et al.Relaxininduces an extracellularmatrix-

degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibro-

sis in a murine model in vivo. J Clin Invest. 1996;98:2739-2745.

38. Seibold JR,KornJH,ClementsPJ, etal. Recombinanthumanrelaxinin thetreat-

ment of scleroderma: a randomized, double-blind, placebo-controlled trial.Ann

Intern Med. 2000;132:871-879.

39. Whitman HH III, CaseDB, Laragh JH,et al.Variableresponse to oralangiotensin-

convertingenzymeblockadein hypertensive sclerodermapatients. ArthritisRheum.

1982;25:241-248.

40. Alpert MA, Pressly TA, Mukerji V, Lambert CR, Mukerji B. Short- and long-term

hemodynamic effects of captopril in patients with pulmonary hypertension and

selected connective tissue disease.Chest. 1992;102:1407-1412.

41. Chang YJ, Spiera H. Renal transplantation in scleroderma.Medicine. 1999;78:

382-385.

42. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epopros-

tenol for pulmonary hypertension due to the scleroderma spectrum of disease:

a randomized, controlled trial.Ann Intern Med. 2000;132:425-434.

43. dela MataJ, Gomez-Sanchez MA,AranzanaM, Gomez-ReinoJJ. Long-termilo-

prost infusion therapy for severe pulmonary hypertension in patients with con-

nective tissue diseases.Arthritis Rheum. 1994;37:1528-1533.

44. Silver EM, Warrick JH, Kinsella MB, Staudt LS, Baumann HM, Strange C. Cyclo-

phosphamideand low-dose prednisonetherapy in patients withsystemic sclerosis

(scleroderma) with interstitial lung disease. J Rheumatol. 1993;20:838-844.

45. Akesson A, Scheja A, Lundin A, Wollheim FA. Improved pulmonary function in

systemicsclerosisafter treatmentwith cyclophosphamide. Arthritis Rheum. 1994;

37:729-735.

46. White B, Moore WC, Wigley FM, Xiai HQ, Wise RA. Cyclophosphamide is

associated with pulmonary function and survival benefit in patients with sclero-

derma and alveolitis.Ann Intern Med. 2000;132:947-954.

47. Le CH, Morales A, Trentham DE. Minocycline in early diffuse scleroderma.Lan-

cet. 1998;352:1755-1756.

48. Kanekurat T, Fukumaru S, Matsushita S, Terask K, Mizoguchis S, Kanzaki T.

Successful treatment of scleroderma with PUVA therapy.J Dermatol. 1996;23:

455-459.

49. SchachnaL, WigleyFM, White B, GelberAC, Rosas I, OrensJB. Lung transplan-

tation in scleroderma:the Johns Hopkinsexperience [abstract]. Arthritis Rheum.

2000;43(suppl):s392.

50. Marcellus DC, Altomonte VL, Farmer ER, et al. Etretinate therapy for refractory

sclerodermatous chronic graft-versus-host disease.Blood. 1999;93:66-70.

51. Martini A, Maccario R, Ravelli A, et al. Marked and sustained improvement two

years after autologous stem cell transplantation in a girl with systemic sclero-

sis.Arthritis Rheum. 1999;42:807-811.

52. Furst DE, McSweeney P, Nash R, et al. High-dose immunosuppressive therapy(HDIT)withautologousstem celltransplantation (SCT)for systemic sclerosis(SSc):

results in the first 8 patients [abstract].Arthritis Rheum. 2000;43(suppl):s392.

53. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison

of chimeric monoclonal antibody to tumour necrosis factor (cA2) versus pla-

cebo in rheumatoid arthritis.Lancet. 1994;344:1105-1110.

54. Spencer-Green G. Etanercept (Enbrel): update on therapeutic use. Ann Rheum

Dis. 2000;59(suppl 1):i46-i49.

55. EllmanMH, McDonaldPA, Hayes FA.Etanercept as treatment fordiffuse sclero-

derma: a pilot study [abstract].Arthritis Rheum. 2000;43(suppl):s392.

56. Oliver SJ,Moreira A, Kaplan G. Reducedfibrosisand normalizationof skinstruc-

turein scleroderma patientstreatedwith thalidomide[abstract]. Arthritis Rheum.

1999;42(suppl):s187.

57. Fleischmajer R, Nedwich A. Generalized morphea: histology of the dermis and

subcutaneous tissue.Arch Dermatol. 1972;106:509-514.

58. Arnett FC, Tan FK, Yosef U, et al. Autoantibodies to the extracellular matrix mi-

crofibrillar protein fibrillin-1 in patients with localized scleroderma. Arthritis

Rheum. 1999;42:2656-2659.59. ElstEF, VanSuijlekom-Smit LW,OranjeAP. Treatmentof linear scleroderma with

oral 1,25-dihydroxyvitamin D3 (calcitriol) in seven children.Pediatr Dermatol.

1999;16:53-58.

60. Hulshof MM, Pavel S, Breedveld FC, Dijkmans AC, Vermeer BJ. Oral calcitriol as

a new therapeutic modality for generalized morphea.Arch Dermatol. 1994;130:

1290-1293.

61. Cunningham BB, Landells IDR, Langman C, Sailer DE, Paller AS. Topical calci-

potriene for morphea/linear scleroderma.J Am Acad Dermatol. 1998;39(pt 2):

211-215.

62. Kerscher M, Meurer M, Sander C, et al. PUVA-bath photochemotherapy for lo-

calized scleroderma.Arch Dermatol. 1996;132:1280-1282.

63. Kerscher M, Volkenandt M, Gruss C,et al.Low-dose phototherapyfor treatment

of localized scleroderma.J Am Acad Dermatol. 1998;38:21-26.

64. Wlaschek M, Briviba K, StricklinP, SiesH, Scharffetter-KochanekK. Singlet oxy-

gen may mediate the ultraviolet-Ainduced synthesis of interstitial collagenase.

J Invest Dermatol. 1995;104:194-198.

65. Wallace CA. The use of methotrexate in childhood rheumatic diseases. ArthritisRheum. 1998;41:381-391.

66. SeygerMMB, vanden HoogenFHJ,de BooT, Elke MGJ, de Jong MD.Low-dose

methotrexate in the treatmentof widespread morphea.J Am Acad Dermatol. 1998;

39:220-225.

67. Uziel Y, Feldman BM, Krafchik BR, Yeung RS, Laxer RM. Methotrexate and cor-

ticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;136:91-

95.



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